The influence of serotonin and other genes on impulsive behavioral aggression and cognitive impulsivity in children with attention-deficit/hyperactivity disorder (ADHD): findings from a family-based association test (FVAT) analysis

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Description/Abstract

Background: Low serotonergic (5-HT) activity correlates with increased impulsive-aggressivebehavior, while the opposite association may apply to cognitive impulsiveness. Both types ofimpulsivity are associated with attention-deficit/hyperactivity disorder (ADHD), and genes offunctional significance for the 5-HT system are implicated in this disorder. Here we demonstratethe separation of aggressive and cognitive components of impulsivity from symptom ratings and test their association with 5-HT and functionally related genes using a family-based association test(FBAT-PC).

Methods: Our sample consisted of 1180 offspring from 607 families from the InternationalMulticenter ADHD Genetics (IMAGE) study. Impulsive symptoms were assessed using the longforms of the Conners and the Strengths and Difficulties parent and teacher questionnaires. Factoranalysis showed that the symptoms aggregated into parent- and teacher-rated behavioral andcognitive impulsivity. We then selected 582 single nucleotide polymorphisms (SNPs) from 14 genesdirectly or indirectly related to 5-HT function. Associations between these SNPs and thebehavioral/cognitive groupings of impulsive symptoms were evaluated using the FBAT-PCapproach.

Results: In the FBAT-PC analysis for cognitive impulsivity 2 SNPs from the gene encodingphenylethanolamine N-methyltransferase (PNMT, the rate-limiting enzyme for adrenalin synthesis)attained corrected gene-wide significance. Nominal significance was shown for 12 SNPs fromBDNF, DRD1, HTR1E, HTR2A, HTR3B, DAT1/SLC6A3, and TPH2 genes replicating reportedassociations with ADHD. For overt aggressive impulsivity nominal significance was shown for 6SNPs from BDNF, DRD4, HTR1E, PNMT, and TPH2 genes that have also been reported to beassociated with ADHD. Associations for cognitive impulsivity with a SERT/SLC6A4 variant (STin2:12 repeats) and aggressive behavioral impulsivity with a DRD4 variant (exon 3: 3 repeats) are alsodescribed.

Discussion: A genetic influence on monoaminergic involvement in impulsivity shown by childrenwith ADHD was found. There were trends for separate and overlapping influences on impulsiveaggressivebehavior and cognitive impulsivity, where an association with PNMT (and arousalmechanisms affected by its activity) was more clearly involved in the latter. Serotonergic anddopaminergic mechanisms were implicated in both forms of impulsivity with a wider range ofserotonergic mechanisms (each with a small effect) potentially influencing cognitive impulsivity.These preliminary results should be followed up with an examination of environmental influencesand associations with performance on tests of impulsivity in the laboratory.